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Osteoprotegerin inhibits aortic valve calcification and preserves valve function in hypercholesterolemic mice.

Weiss RM, Lund DD, Chu Y, Brooks RM, Zimmerman KA, El Accaoui R, Davis MK, Hajj GP, Zimmerman MB, Heistad DD - PLoS ONE (2013)

Bottom Line: There are no rigorously confirmed effective medical therapies for calcific aortic stenosis.Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known.OPG or vehicle (N = 12 each) was administered from 6 to 12 months of age, followed by echocardiographic evaluation of valve function, followed by histologic evaluation.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America. robert-weiss@uiowa.edu

ABSTRACT

Background: There are no rigorously confirmed effective medical therapies for calcific aortic stenosis. Hypercholesterolemic Ldlr (-/-) Apob (100/100) mice develop calcific aortic stenosis and valvular cardiomyopathy in old age. Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known.

Objectives: To determine the impact of pharmacologic treatment with OPG upon aortic valve calcification and valve function in aortic stenosis-prone hypercholesterolemic Ldlr (-/-) Apob (100/100) mice.

Methods: Young Ldlr (-/-) Apob (100/100) mice (age 2 months) were fed a Western diet and received exogenous OPG or vehicle (N = 12 each) 3 times per week, until age 8 months. After echocardiographic evaluation of valve function, the aortic valve was evaluated histologically. Older Ldlr (-/-) Apob (100/100) mice were fed a Western diet beginning at age 2 months. OPG or vehicle (N = 12 each) was administered from 6 to 12 months of age, followed by echocardiographic evaluation of valve function, followed by histologic evaluation.

Results: In Young Ldlr (-/-) Apob (100/100) mice, OPG significantly attenuated osteogenic transformation in the aortic valve, but did not affect lipid accumulation. In Older Ldlr (-/-) Apob (100/100) mice, OPG attenuated accumulation of the osteoblast-specific matrix protein osteocalcin by ∼80%, and attenuated aortic valve calcification by ∼ 70%. OPG also attenuated impairment of aortic valve function.

Conclusions: OPG attenuates pro-calcific processes in the aortic valve, and protects against impairment of aortic valve function in hypercholesterolemic aortic stenosis-prone Ldlr (-/-) Apob (100/100) mice.

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Masson’s Trichrome staining for collagen in Older mice.Collagen (dark blue) was equally abundant in valves of vehicle-treated mice (A,C) and OPG-treated mice (B,D). N = 12; p = NS for Veh vs. OPG.
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pone-0065201-g007: Masson’s Trichrome staining for collagen in Older mice.Collagen (dark blue) was equally abundant in valves of vehicle-treated mice (A,C) and OPG-treated mice (B,D). N = 12; p = NS for Veh vs. OPG.

Mentions: OPG did not attenuate fibrosis of the valve, assessed using Masson’s Trichrome staining, significantly in Older LA mice (Figure 7). Because of the importance of differentiating the selective effect of OPG on valve calcification, but not on fibrosis, we performed confirmatory studies using Picrosirius Red staining for valve fibrosis, and again found no significant effect of OPG treatment upon valve fibrosis (Figure S3).


Osteoprotegerin inhibits aortic valve calcification and preserves valve function in hypercholesterolemic mice.

Weiss RM, Lund DD, Chu Y, Brooks RM, Zimmerman KA, El Accaoui R, Davis MK, Hajj GP, Zimmerman MB, Heistad DD - PLoS ONE (2013)

Masson’s Trichrome staining for collagen in Older mice.Collagen (dark blue) was equally abundant in valves of vehicle-treated mice (A,C) and OPG-treated mice (B,D). N = 12; p = NS for Veh vs. OPG.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675204&req=5

pone-0065201-g007: Masson’s Trichrome staining for collagen in Older mice.Collagen (dark blue) was equally abundant in valves of vehicle-treated mice (A,C) and OPG-treated mice (B,D). N = 12; p = NS for Veh vs. OPG.
Mentions: OPG did not attenuate fibrosis of the valve, assessed using Masson’s Trichrome staining, significantly in Older LA mice (Figure 7). Because of the importance of differentiating the selective effect of OPG on valve calcification, but not on fibrosis, we performed confirmatory studies using Picrosirius Red staining for valve fibrosis, and again found no significant effect of OPG treatment upon valve fibrosis (Figure S3).

Bottom Line: There are no rigorously confirmed effective medical therapies for calcific aortic stenosis.Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known.OPG or vehicle (N = 12 each) was administered from 6 to 12 months of age, followed by echocardiographic evaluation of valve function, followed by histologic evaluation.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America. robert-weiss@uiowa.edu

ABSTRACT

Background: There are no rigorously confirmed effective medical therapies for calcific aortic stenosis. Hypercholesterolemic Ldlr (-/-) Apob (100/100) mice develop calcific aortic stenosis and valvular cardiomyopathy in old age. Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known.

Objectives: To determine the impact of pharmacologic treatment with OPG upon aortic valve calcification and valve function in aortic stenosis-prone hypercholesterolemic Ldlr (-/-) Apob (100/100) mice.

Methods: Young Ldlr (-/-) Apob (100/100) mice (age 2 months) were fed a Western diet and received exogenous OPG or vehicle (N = 12 each) 3 times per week, until age 8 months. After echocardiographic evaluation of valve function, the aortic valve was evaluated histologically. Older Ldlr (-/-) Apob (100/100) mice were fed a Western diet beginning at age 2 months. OPG or vehicle (N = 12 each) was administered from 6 to 12 months of age, followed by echocardiographic evaluation of valve function, followed by histologic evaluation.

Results: In Young Ldlr (-/-) Apob (100/100) mice, OPG significantly attenuated osteogenic transformation in the aortic valve, but did not affect lipid accumulation. In Older Ldlr (-/-) Apob (100/100) mice, OPG attenuated accumulation of the osteoblast-specific matrix protein osteocalcin by ∼80%, and attenuated aortic valve calcification by ∼ 70%. OPG also attenuated impairment of aortic valve function.

Conclusions: OPG attenuates pro-calcific processes in the aortic valve, and protects against impairment of aortic valve function in hypercholesterolemic aortic stenosis-prone Ldlr (-/-) Apob (100/100) mice.

Show MeSH
Related in: MedlinePlus